A key step in the synthesis of the reverse transcriptase inhibitor, (-)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl- 1,4-dihydro-2H-3,1-benzoxazin-2-one, also known as DMP-266, is the cyclization of the amino alcohol using phosgene.
The synthesis of DMP-266 and structurally similar reverse transcriptase inhibitors are disclosed in U.S. Pat. No. 5,519,021 and the corresponding PCT International Patent Application WO 95/20389, which published on Aug. 3, 1995. Additionally, the asymmetric synthesis of an enantiomeric benzoxazinone by a highly enantioselective acetylide addition and cyclization sequence that has been described by Thompson, et al., Tetrahedron Letters 1995, 36, 8937-8940, as well as the PCT publication, WO 96/37457, which published on Nov. 28, 1996.
The instant invention discloses an efficient method for the cyclization of an amino alcohol of formula ##STR1## using a chloroformate and a base in a solvent to give the 1,4-dihydro-2H-3,1-benzoxazin-2-one ##STR2##
This cyclization method employs an aryl or alkyl chloroformate and avoids the use of phosgene, a toxic and highly hazardous gas, which requires special handling.